The Impact of Pazopanib on the Cardiovascular System

Abstract

Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system.

Keywords: hypertension; pazopanib; renal cell carcinoma; tyrosine kinase inhibitors.

Figure 1.

Vascular endothelial growth factor (VEGF) signaling in endothelial cells is vital for cell survival and vasodilation. Vascular endothelial growth factor binds to VEGF receptor 2 (VEGFR-2) inducing a conformational change that activates Src, phosphoinositide 3-kinase (PI3K), and phospholipase C (PLC; green arrows). Phosphoinositide 3-kinase activity is a significant suppressor of apoptosis, leading to cell survival (green arrow). Additionally, PI3K is an activator of protein kinase B (AKT) which stimulates the production nitric oxide (NO) through activation of endothelial NO synthase (eNOS), leading to vasodilation (green arrows). Phospholipase C contributes to vaso-dilation through activation of cyclooxygenase 2 (COX2) which produces prostacyclin 2 (PGI₂; green arrows). Pazopanib inhibits the intracellular ATP-binding domain of VEGFR-2 (red arrow). Activation of VEGFR-2 suppresses the production of endothelin-1 (a potent vasoconstrictor; red arrow) by an unknown mechanism.

Figure 2.

Pazopanib inhibits the intracellular ATP-binding domain of many growth factors (red arrow) due to the high conservation of this domain across the kinome. Basal activity of these receptors contributes to cell survival and proliferation through the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR1 pathways (green arrows). Protein kinase B (AKT) is a suppressor of Bcl-2 associated death promoter (BAD; red arrow), an inducer of apoptosis. Mechanistic target of rapamycin 1 (mTOR1) activity contributes to cell growth and hypertrophy (green arrow). Pazopanib also inhibits nonreceptor kinases RAF-1 and B-RAF (red arrows).